Approximately 5 million Americans currently suffer from Alzheimer's disease (AD) a neurodegenerative disorder characterized by progressive impairment of cognitive function and emotional and sleep disturbances. This laboratory has developed cell culture and mouse models of AD, and have used these models to elucidate the biochemical and molecular events responsible for neuronal dysfunction and death in AD. We have found that there are abnormalities in lipid metabolism in the brains of patients with AD. Specifically, levels of cholesterol and long-chain ceramides are increased. Studies of experimental animal and cell culture models of AD suggest that increased oxidative stress, associated with amyloid deposition is responsible for the lipid abnormalities. Antioxidants and drugs that prevent the production of ceramides protect neurons from being damaged and killed by amyloid suggesting an important role for the lipid abnormalities in the disease process. In other studies we have identified a novel protein called Herp (homocysteine responsive endoplasmic reticulum protein) that can protect neurons from being damaged and killed by amyloid and a presenilin mutation. Finally, we have found that dietary restriction can protect neurons from being damaged and killed in animal models of AD, and that this beneficial effect of dietary restriction involves stimulation of the production of brain-derived neurotrophic factor (BDNF).